A bone tissue is a dynamic tissue in which breaking and formation are continuously repeated. The breaking, i.e. resorption of bone and succeeding bone formation collectively constitute a phenomenon called remodeling, and through the remodeling, the bone tissue is continuously reconstructed throughout life. If the balance between bone resorption and bone formation is destroyed, various kinds of metabolic bone diseases are developed. When bone resorption exceeds bone formation, bone mass gradually decreases. Typical diseases in this case are osteomalacia and osteoporosis.
A disease whose bone resorption is more accelerated than osteoporosis is Paget's disease of bone. The cause of Paget's disease of bone is not known yet; however, a fingerprint like pattern of the osteoclast nucleus of Paget's disease of bone suggests that the disease is caused by virus. In a patient with Paget's disease of bone, bone metabolism turnover is extremely active on disease sites, and the disease often develops on pelvises, femurs, skulls, cervical vertebrae, vertebrae, clavicles, humeri or the like. An osteoclast activated to the utmost has an extremely large size, contains a number of nuclei and performs active bone resorption. When the restoration by osteoblasts is activated to the utmost, lamellar bones and bone trabeculae having coarse net shapes and large thickness are formed. Even in the case of dense calcification, mosaic layered collagen forms weak bone which is structurally fat (Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, fourth edition, p. 415–425, 1999, Lippincott Williams & Wilkins).
Recently, it has become clear that osteoclast precursor cells and osteoclasts collected from patients with Paget's disease of bone have 1α,25-dihydroxyvitamin D3 receptors, and the sensitivity to 1α,25-dihydroxyvitamin D3 of the osteoclast precursor cells and osteoclasts were 10 to 100 times larger than the sensitivity of osteoclast precursor cells and osteoclasts collected from normal adults (J. Bone Miner. Res., vol. 15, 228–236 (2000)). Further, it has been reported that serum of patients with Paget's disease of bone contains 1α,25-dihydroxyvitamin D3 at a concentration same as that of normal adults (50–150 pM; 20–60 pg/ml serum) (J. Bone Miner. Res., vol. 5, 1121–1126 (1990) and J. Bone Miner. Res., vol. 9. 81–85 (1994)). This shows that in osteoclast precursor cells of normal adults, osteoclast formation is virtually not induced by 1α,25-dihydroxyvitamin D3 of physiological concentration and, on the contrarily, in osteoclast precursor cells collected from patients with Paget's disease of bone, the osteoclast formation is stimulated in the presence of 1α,25-dihydroxyvitamin D3 of physiological concentration, and bone resorption is accelerated. Furthermore, it was reported that when nucleocapsid genes of measles viruses are transduced into osteoclast precursor cells of normal adults, and 1α,25-dihydroxyvitamin D3 solution of physiological concentration is made to act on the cells, osteoclasts having a shape completely identical to the osteoclasts collected from patients with Paget's disease of bone are formed, and they actively perform bone resorption (J. Clin. Invest. vol. 105, 606–614 (2000)). The above findings suggest that the rapid acceleration of bone resorption observed in the patients with Paget's disease of bone is attributable to the acceleration of osteoclast formation and the activation of the formed osteoclasts caused by the enhancement of the sensitivity to 1α,25-dihydroxyvitamin D3 of osteoclast precursor cells with measles virus infection.
In patients with Paget's disease of bone, the acceleration of sensitivity to 1α,25-dihydroxyvitamin D3 is observed only on the bone in which the bone resorption has been stimulated, and thereby, it seems that the abnormalities of the disease exist in osteoclast precursor cells and osteoclasts. Further, judging from the fact that the sensitivity to 1α,25-dihydroxyvitamin D3 is accelerated at least 100 times more that of normal adults, it is difficult to consider that the cause of the acceleration of the sensitivity is attributable to the increase of the number of vitamin D receptors and the increase of the binding constant of vitamin D receptor to 1α,25-dihydroxyvitamin D3, and accordingly it is presumed that “coactivator”, that is, a transcription factor to a vitamin D receptor in an osteoclast precursor cell and an osteoclast of a patient with Paget's disease of bone is expressed. If this presumption is correct, a compound suppressing such an expression of a transcription factor may be useful as a treating agent for Paget's disease of bone and to become a treating agent which is more fundamental and useful compared with a bone resorption suppressor, such as a bisphosphonate preparation and a calcitonin preparation, which is presently used.